DESCRIPTION (provided by investigator): Although psychosocial stress has been hypothesized to play a role in the etiology of cardiovascular disease, empirical verifications of the effects of stress and the biological mechanisms through which stress operates remain rare. A major limitation has been the absence of population studies with direct biologic measures of stress (such as measures of levels of stress hormones), so that their link to social antecedents and to biological precursors of cardiovascular disease can be studied. It has also become increasingly apparent that social conditions and stressors must interact with genetic makeup, and that some of these exposures may modify gene expression through changes in DNA methylation but few population studies have comprehensively investigated the gene-environment interactions and epigenetic changes related to psychosocial factors. A major goal of this project is to better understand the ways in which socially patterned stress interacts with genetics and biology to influence cardiovascular-related outcomes. Using data from the Multiethnic Study of Atherosclerosis, a large, multiethnic population sample, we propose to investigate long-term associations of the stress response (as characterized by multiple measures of stress hormones) with social/psychosocial antecedents and cardiovascular-related outcomes, as well as modifications of the stress response by variations in selected candidate genes, and links between psychosocial factors and epigenetic changes. The Specific Aims of the project are: (1) To examine associations of repeat measures of stress hormones with social and psychosocial factors and with biological precursors of cardiovascular disease including inflammation/hemostasis and measures of insulin resistance and adiposity; (2) To examine interactions between cortisol levels and polymorphisms of the glucocorticoid receptor gene with respect to cardiovascular-related outcomes; (3) To examine the extent to which polymorphisms of biologically relevant genes modify the response to a psychological stress challenge; and (4) To examine epigenetic changes (DNA methylation) of the glucocorticoid receptor gene as well as genomic DNA methylation and their association with (a) lifecourse social exposures; (b) cortisol and hemodynamic responses to a stress challenge; and (c) biological parameters previously linked to stress exposures. Our study will enhance our understanding not only of the epidemiologic links between stress and cardiovascular disease but also of the biologic mechanisms (involving genetic polymorphisms and changes to gene expression) through which these effects may be mediated. By illustrating how the study of genetic variability, biological markers, and social conditions can be integrated to enhance our understanding of the causes of ill health our project has the potential for contributing to major paradigmatic change in health research.